scholarly journals Increased blood BACE1 activity as a potential common pathogenic factor of vascular dementia and late onset Alzheimer's disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Giovanni Zuliani ◽  
Alessandro Trentini ◽  
Valentina Rosta ◽  
Remo Guerrini ◽  
Salvatore Pacifico ◽  
...  
Keyword(s):  
Vascular Dementia ◽  
Late Onset ◽  
Mixed Dementia ◽  
Vascular Events ◽  
Key Enzyme ◽  
Amyloid Aβ ◽  
Cerebrovascular Insult ◽  
First Time ◽  
Bace1 Activity

Abstract Late onset Alzheimer disease (LOAD) is traditionally considered as a separate disease from vascular dementia (VAD). However, growing evidence suggests that β-amyloid (Aβ) accumulation, that initiates LOAD-related neurodegeneration, is preceded by vascular events. Previous in vitro studies showed that β-secretase 1 (BACE1), the key-enzyme of amyloidogenesis, is upregulated by cerebrovascular insult; moreover, its activity is increased both in brain and serum of LOAD patients. We aimed to investigate whether BACE1 serum activity is altered also in dementias related, or not, to cerebrovascular disease. Thus, we evaluated serum BACE1 activity in a sample of individuals, including patients with LOAD (n. 175), VAD (n. 40), MIXED (LOAD/VAD) dementia (n. 123), other types of dementia (n. 56), and healthy Controls (n. 204). We found that BACE1 was significantly higher not only in LOAD (+ 30%), but also in VAD (+ 35%) and MIXED dementia (+ 22%) (p < 0.001 for all), but not in the other types of dementia (+ 10%). Diagnostic accuracy was 77% for LOAD, 83% for VAD, and 77% for MIXED dementia. In conclusion, we showed for the first time that the increase in peripheral BACE1 activity is a common feature of LOAD and VAD, thus underlying a further pathogenic link between these two forms of dementia.

Abstract 278: Enhanced Cystathionine ß-Synthase Nitration in Diet-Induced Hyperhomocysteinemic Rats Accelerates the Progression of Hyperhomocysteinemia

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Wen Wang ◽  
Hui Zhang ◽  
Wei Liu ◽  
Teng Liu ◽  
Lu Ma ◽  
...  
Keyword(s):  
Independent Risk Factor ◽  
Normal Diet ◽  
Nutritional Deficiencies ◽  
Etiologic Factor ◽  
Nitrative Stress ◽  
Transsulfuration Pathway ◽  
Key Enzyme ◽  
High Level ◽  
First Time

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases,which may be caused by genetic deficiencies in enzymes responsible for remethylation or transsulfuration of homocysteine, nutritional deficiencies in vitamins, or excessive intakes of methionine. Since transsulfuration pathway is the only irreversible pathway in homocysteine metabolism, its key enzyme cystathionine β-synthase is vital in terminal removement of homocysteine. In addition, Studies have observed that enhanced nitrative stress in hyperhomocysteinemic rats could induce cardiovascular injuries, and peroxynitrite stimulation in vitro resulting in decreased bioactivity of cystathionine β-synthase. Therefore, to determine the contribution of nitrative stress to progression of hyperhomocysteinemia, and how it is related to cystathionine β-synthase, we used three groups of rats (Con with normal diet, HHcy with 2.5% methionine diet, HHcy+FeTMPyP with 2.5% methionine diet +FeTMPyP) to observe the effects of nitrative stress on cystathionine β-synthase. Results showed that in diet-induced hyperhomocysteinemic rats, tHcy levels and nitrative stress increased, surprisingly, pretreatment with peroxynitrite scavenger FeTMPyP ameliorated the level of tHcy as well as nitrative stress. Further experiments showed cystathionine β-synthase bioactivity in HHcy rats was less potent than other groups yet described, and the level of cystathionine β-synthase nitration was the most significant,while the entire trends reversed after FeTMPyP pretreatment. In conclusion, these results highlight for the first time that in diet-induced hyperhomocysteinemic rats, cystathionine β-synthase bioactivity reduction is not just a traditional etiologic factor, but rather an outcome of hyperhomocysteinemia, and resulting from the high level of nitrative stress caused by hyperhomocysteinemia, the cystathionine β-synthase nitration plays a mutual role in hyperhomocysteinemia development via causing the metabolic disorder of homocysteine. These findings may shed a novel light on the homocystine-lowering target of hyperhomocysteinemia.

scholarly journals pHluorin-BACE1-mCherry Acts as a Reporter for the Intracellular Distribution of Active BACE1 In Vitro and In Vivo

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 474 ◽  
Author(s):  
Lu Zhao ◽  
Yang Zhao ◽  
Fu-Lei Tang ◽  
Lei Xiong ◽  
Ce Su ◽  
...  
Keyword(s):  
Ph Dependence ◽  
Ph Sensor ◽  
Maximal Activity ◽  
Ph Changes ◽  
Fluorescence Characteristics ◽  
A Subunit ◽  
Amyloid Aβ ◽  
Bace1 Activity

β-site APP-cleaving enzyme 1 (BACE1) initiates amyloid precursor protein (APP) cleavage and β-amyloid (Aβ) production, a critical step in the pathogenesis of Alzheimer’s disease (AD). It is thus of considerable interest to investigate how BACE1 activity is regulated. BACE1 has its maximal activity at acidic pH and GFP variant—pHluorin—displays pH dependence. In light of these observations, we generated three tandem fluorescence-tagged BACE1 fusion proteins, named pHluorin-BACE1-mCherry, BACE1-mCherry-pHluorin and BACE1-mCherry-EGFP. Comparing the fluorescence characteristics of these proteins in response to intracellular pH changes induced by chloroquine or bafilomycin A1, we found that pHluorin-BACE1-mCherry is a better pH sensor for BACE1 because its fluorescence intensity responds to pH changes more dramatically and more quickly. Additionally, we found that (pro)renin receptor (PRR), a subunit of the v-ATPase complex, which is critical for maintaining vesicular pH, regulates pHluorin’s fluorescence and BACE1 activity in pHluorin-BACE1-mCherry expressing cells. Finally, we found that the expression of Swedish mutant APP (APPswe) suppresses pHluorin fluorescence in pHluorin-BACE1-mCherry expressing cells in culture and in vivo, implicating APPswe not only as a substrate but also as an activator of BACE1. Taken together, these results suggest that the pHluorin-BACE1-mCherry fusion protein may serve as a useful tool for visualizing active/inactive BACE1 in culture and in vivo.

Somatic Embryogenesis and In vitro Plant Regeneration in Vigna trilobata (L.) Verd. - A Potential Pasture Legume

1970 ◽  
Vol 19 (1) ◽  
pp. 89-99
Author(s):  
K. Choudhary ◽  
M. Singh ◽  
M. S. Rathore ◽  
N. S. Shekhawat
Keyword(s):  
Somatic Embryogenesis ◽  
Growth Regulators ◽  
Somatic Embryos ◽  
Basal Medium ◽  
Long Term Study ◽  
Continuous Application ◽  
First Time ◽  
Pasture Legume

This long term study demonstrates for the first time that it is possible to propagate embryogenic Vigna trilobata and to subsequently initiate the differentiation of embryos into complete plantlets. Initiation of callus was possible on 2,4-D. Somatic embryos differentiated on modified MS basal nutrient medium with 1.0 mg/l  of 2,4-D and 0.5 mg/l  of Kn. Sustained cell division resulted in globular and heart shape stages of somatic embryos. Transfer of embryos on to a fresh modified MS basal medium with 0.5 mg/l of Kn and 0.5 mg/l of GA3 helped them to attain maturation and germination. However, the propagation of cells, as well as the differentiation of embryos, were inhibited by a continuous application of these growth regulators. For this reason, a long period on medium lacking these growth regulators was necessary before the differentiation of embryos occurred again. The consequences for improving the propagation of embryogenic cultures in Vigna species are discussed. Key words: Pasture  legume, Vigna trilobata, Globular, Heart shape, somatic embryogenesis D.O.I. 10.3329/ptcb.v19i1.4990 Plant Tissue Cult. & Biotech. 19(1): 89-99, 2009 (June)

Dwindling status of Epimedium Elatum (Morren & Decne) and its geographical distribution in Kashmir Himalaya, India

2018 ◽  
pp. 47-52
Keyword(s):  
Medicinal Plant ◽  
Biological Activities ◽  
Conservation Status ◽  
Natural Populations ◽  
Culture Techniques ◽  
Kashmir Himalayas ◽  
Near Future ◽  
First Time ◽  
Tissue Culture Techniques

Epimedium elatum (Morren & Decne) of family Berberidaceace is a rare perennial medicinal plant, endemic to high altitude forests of Northwestern Himalayas in India. Ethnobotanically, it has been used as an ingredient for treatment of bone-joint disorders, impotence and kidney disorders in Kashmir Himalayas. Phytochemically, it is rich in Epimedin ABC and Icariin; all of these have been demonstrated to possess remarkable biological activities like PDE-5 inhibition (treatment of erectile dysfunction), anticancer, antiosteoporosis antioxidant and antiviral properties. The present investigation reports its traditional usage, comprehensive distribution and conservation status from twenty ecogeographical regions in Kashmir Himalayas, India. The species was reported from Gurez valley for the first time. Numerous threats like excessive grazing, deforestration, habitat fragmentation, tourism encroachment, landslides and excessive exploitation have decreased its natural populations in most of the surveyed habitats. Consequently, its existence may become threatened in near future if timely conservation steps are not taken immediately by concerned stakeholders involved in medicinal plant research. Moreover, use of plant tissue culture techniques is recommended for development of its in vitro propagation protocols. Therefore, introduction of this medicinal plant in botanical gardens, protected sites and development of monitoring programmes are needed for its immediate conservation in Northwestern Himalayas, India.

Structure-Reactivity Relationships on Substrates and Inhibitors of the Lysine Deacylase Sirtuin 2 from Schistosoma Mansoni (SmSirt2)

2019 ◽  
Author(s):  
Daria Monaldi ◽  
Dante Rotili ◽  
Julien Lancelot ◽  
Martin Marek ◽  
Nathalie Wössner ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Human Cancer ◽  
Egg Laying ◽  
Human Cancer Cells ◽  
Parasite Survival ◽  
Survival And Reproduction ◽  
Emergence Of Resistance ◽  
First Time ◽  
Parasitic Life Cycle

The only drug for treatment of Schistosomiasis is Praziquantel, and the possible emergence of resistance makes research on novel therapeutic agents necessary. Targeting of Schistosoma mansoni epigenetic enzymes, which regulate the parasitic life cycle, emerged as promising approach. Due to the strong effects of human Sirtuin inhibitors on parasite survival and reproduction, Schistosoma sirtuins were postulated as therapeutic targets. In vitro testing of synthetic substrates of S. mansoni Sirtuin 2 (SmSirt2) and kinetic experiments on a myristoylated peptide demonstrated lysine long chain deacylation as an intrinsic SmSirt2 activity for the first time. Focused in vitro screening of the GSK Kinetobox library and structure-activity relationships (SAR) of identified hits, led to the first SmSirt2 inhibitors with activity in the low micromolar range. Several SmSirt2 inhibitors showed potency against both larval schistosomes (viability) and adult worms (pairing, egg laying) in culture without general toxicity to human cancer cells.<br>

α-Glucosidase Inhibition and Docking Studies of 5-Deoxyflavonols and Dihydroflavonols Isolated from Abutilon pakistanicum

2019 ◽  
Vol 23 (17) ◽  
pp. 1857-1866
Author(s):  
Munawar Hussain ◽  
Zaheer Ahmed ◽  
Shamsun N. Khan ◽  
Syed A. A. Shah ◽  
Rizwana Razi ◽  
...  
Keyword(s):  
Methanolic Extract ◽  
Docking Studies ◽  
Hydroxyl Group ◽  
Coumaric Acid ◽  
In Vitro Activity ◽  
Aerial Parts ◽  
First Time ◽  
Acid Esters ◽  
Phenol Moiety

Three new 5-deoxyflavonoid and dihydroflavonoids 2, 3 and 4 have been isolated from the methanolic extract of Abutioln pakistanicum aerial parts, for which structures were elucidated explicitly by extensive MS- and NMR-experiments. In addition to these, 3,7,4′-trihydroxy-3′-methoxy flavonol (1) is reported for the first time from Abutioln pakistanicum. Compound 2 and 4 are p-coumaric acid esters while compounds 2–4 exhibited α-glucosidase inhibitory activity. Docking studies indicated that the ability of flavonoids 2, 3 and 4 to form multiple hydrogen bonds with catalytically important residues is decisive hence is responsible for the inhibition activity. The docking results signified the observed in-vitro activity quite well which is in accordance with previously obtained conclusion that phenol moiety and hydroxyl group are critical for the inhibition of α-glucosidase enzyme.

Exploring the Role of Aggregated Proteomes in the Pathogenesis of Alzheimer’s Disease

2020 ◽  
Vol 21 (12) ◽  
pp. 1164-1173
Author(s):  
Siju Ellickal Narayanan ◽  
Nikhila Sekhar ◽  
Rajalakshmi Ganesan Rajamma ◽  
Akash Marathakam ◽  
Abdullah Al Mamun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Early Onset ◽  
Late Onset ◽  
Precursor Protein ◽  
Brain Disorder ◽  
Amyloid Aβ ◽  
T Tau

: Alzheimer’s disease (AD) is a progressive brain disorder and one of the most common causes of dementia and death. AD can be of two types; early-onset and late-onset, where late-onset AD occurs sporadically while early-onset AD results from a mutation in any of the three genes that include amyloid precursor protein (APP), presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2). Biologically, AD is defined by the presence of the distinct neuropathological profile that consists of the extracellular β-amyloid (Aβ) deposition in the form of diffuse neuritic plaques, intraneuronal neurofibrillary tangles (NFTs) and neuropil threads; in dystrophic neuritis, consisting of aggregated hyperphosphorylated tau protein. Elevated levels of (Aβ), total tau (t-tau) and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) have become an important biomarker for the identification of this neurodegenerative disease. The aggregation of Aβ peptide derived from amyloid precursor protein initiates a series of events that involve inflammation, tau hyperphosphorylation and its deposition, in addition to synaptic dysfunction and neurodegeneration, ultimately resulting in dementia. The current review focuses on the role of proteomes in the pathogenesis of AD.

Trans-sialidase Associated with Atherosclerosis: Defining the Identity of a Key Enzyme Involved in the Pathology

2019 ◽  
Vol 20 (9) ◽  
pp. 938-941
Author(s):  
Victor Y. Glanz ◽  
Veronika A. Myasoedova ◽  
Andrey V. Grechko ◽  
Alexander N. Orekhov
Keyword(s):  
Acid Metabolism ◽  
Research Subject ◽  
Disease Pathogenesis ◽  
Sialidase Activity ◽  
Ph Values ◽  
Ldl Particles ◽  
Optimum Ph ◽  
Key Enzyme ◽  
St6gal I

Atherosclerosis is associated with the increased trans-sialidase activity, which can be detected in the blood plasma of atherosclerosis patients. The likely involvement in the disease pathogenesis made this activity an interesting research subject and the enzyme that may perform such activity was isolated and characterized in terms of substrate specificity and enzymatic properties. It was found that the enzyme has distinct optimum pH values, and its activity was enhanced by the presence of Ca2+ ions. Most importantly, the enzyme was able to cause atherogenic modification of lowdensity lipoprotein (LDL) particles in vitro. However, the identity of the discovered enzyme remained to be defined. Currently, sialyltransferases, mainly ST6Gal I, are regarded as major contributors to sialic acid metabolism in human blood. In this mini-review, we discuss the possibility that atherosclerosis- associated trans-sialidase does, in fact, belong to the sialyltransferases family.

Antimutagenic, Antiproliferative and Antioxidant Properties of Sea Grape Leaf Extract Fractions (Coccoloba uvifera L.)

2021 ◽  
Vol 21 ◽  
Author(s):  
Jorge A. Ramos-Hernández ◽  
Montserrat Calderón-Santoyo ◽  
Armando Burgos-Hernández ◽  
Joel S. García- Romo ◽  
Arturo Navarro-Ocaña ◽  
...  
Keyword(s):  
Antioxidant Properties ◽  
In Vitro Tests ◽  
Antimutagenic Activity ◽  
Hexane Extraction ◽  
Biological Potential ◽  
Hct 116 ◽  
Pharmaceutical Industries ◽  
Grape Leaf ◽  
First Time

Background: Cancer is a disease characterized by the invasion and uncontrolled growth of cells. One of the best ways to minimize the harmful effects of mutagens is through the use of natural antimutagens. In this regard, the search for new antimutagens that act in the chemoprevention could represent a promising field in this area. Objective: In this study biological potential of 11 fractions from Coccoloba uvifera L. leaf hexane extract was evaluated by several in vitro tests. Methods: Leaves were lyophilized and hexane extraction was performed. The extract was fractionated by column chromatography with hexane, ethyl acetate, and methanol. The antimutagenic (Ames test), antiproliferative (MTT test), and antioxidant capacity (DPPH, ABTS, and ferrous ion chelation) of the fractions were evaluated. Results: Fractions 4, 6, 8, and 9 have antimutagenic activity (against sodium azide in strain TA100), fraction 11 showed antiproliferative capacity (IC50 of 24 ± 9 μg/mL in cells of HCT 116). The fractions with the highest activity were analyzed by HPLC-MS and lupeol, acacetin, and β-sitosterol were identified. Conclusion: This study demonstrates, for the first time, the bioactivity of C. uvifera leaf as a new source of high biological value compounds (HBVC), which can be of interest to the food and pharmaceutical industries.

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